It is called Pcsk9 and is the gene involved in regulating cholesterol levels in the blood. Some mutated variants of this gene cause familial hypercholesterolemia: a rare genetic condition characterized by a high risk of serious cardio- and cerebro-vascular diseases, such as heart attack and stroke, even at a young age. A team of Italian scientists has developed a strategy to turn off the defective gene without modifying the DNA, demonstrating for the first time in vivo – in a model organism – the long-term effectiveness of this advanced therapeutic approach which, in fact, turns off pathological genes with mechanisms called epigenetic, to be carried out only once in a lifetime.
The researchers did the first study on the gene responsible for hypercholesterolemia and earned the pages of the journal 'Nature'. But others could follow, given that the strategy could also be used for other diseases. After genetic editing (a targeted modification of the DNA sequence of a gene), therefore, comes 'epigenetic' editing: the possibility of modulating the level of activation of a gene without intervening on its sequence. The work was signed by the team of Angelo Lombardo, head of the Laboratory of Epigenetic Regulation and Targeted Genome Modification at the San Raffaele Telethon Institute for Gene Therapy (Sr-Tiget) in Milan and professor at the Vita-Salute San Raffaele University (UniSr).
Pcsk9 in the sights of scientists. “In some patients with the disease, the gene is more active than normal and this leads to a lower effectiveness of the liver cells in 'capturing' the so-called bad cholesterol, LDL. The consequence is an increase in cholesterol levels in the blood, in turn once responsible for the increase in cardiovascular risk”, explains Lombardo. Some therapies that aim to inactivate this gene in patients with familial hypercholesterolemia have already arrived in the clinic, including a gene editing platform that acts on the DNA sequence, and others are in an advanced phase of testing. For various reasons, however, Pcsk9 also represents an excellent target for the newest epigenetic silencing technology.
What is it about? Epigenetics is a set of mechanisms that regulates the expression state of genes, i.e. whether they are turned on or off, without intervening on the DNA sequence. For example, it may involve the addition or elimination of particular chemical groups to the DNA molecule, such as to make it more or less accessible to the cellular machinery that initiates the process responsible for protein synthesis. Epigenetic silencing therefore means the possibility of turning off the expression of a target gene by intervening precisely on these mechanisms. “It is a sort of molecular switch that prevents the conversion of the information contained in the target gene into the corresponding protein”, clarifies Lombardo, one of the world pioneers of this technology.
The approach – the experts report – immediately gave excellent results in in vitro experiments, in cell lines, but an in vivo test was still missing: a fundamental piece to be able to move from the laboratory bench to the patient's bed. And this is the proof obtained by Lombardo's group for Pcsk9. First, the researchers developed molecules (editors in jargon) programmed to recognize and turn off this gene, adding particular chemical groups to its sequence. The second step was to encapsulate the editors in lipid nanoparticles, similar to those used for mRna-based anti-Covid vaccines, which were finally administered in mouse models. “We have effectively confirmed that, in the experimental models treated, Pcsk9 is turned off in a stable and long-term way”, underlines Martino Alfredo Cappelluti, first author of the study.
This result now opens up various perspectives, starting from the development of drugs based on epigenetic silencing for hypercholesterolemia, both familial and acquired, i.e. not caused by mutations in single genes and decidedly more common. “Compared to other innovative treatments directed against Pcsk9 – comments Lombardo – this approach could have numerous advantages, as it is a therapy to be carried out only once in a lifetime, which does not modify the DNA sequence (with all the risks that this could entail) and with potentially reversible effects. Furthermore, the demonstration of efficacy obtained constitutes a very solid basis for developing epigenetic silencing strategies directed always at the liver for other diseases, such as hepatitis B, but also at other organs, such as the central nervous system” .
Precisely with the transfer of research results to the patient in mind, already in 2019 the Telethon Foundation and the San Raffaele hospital, together with Lombardo and Luigi Naldini, scientific creators, had founded a start-up, EpsilenBio, dedicated to the development of an epigenetic silencing platform for the treatment of various diseases. The start-up was financed by Sofinnova-Telethon and acquired 2 years later by the American Chroma Medicine Inc. of Boston, one of the most important epigenetic silencing companies in the world, of which Lombardo is co-founder.
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